Hejazi, N. | bioRxiv Science

bioRxiv2025

Growth inhibitory effect of cerebrospinal fluid of multiple sclerosis patients on HFF2 cells

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Occurrence of immunogenic cell death (ICD) in this disease and expression of ICD markers in the CSF of MS patients are documented. However, cytotoxic effect of MS patients cerebrospinal fluid (CSF) on the cells is not reported. To evaluate the cytotoxic impact of CSF from MS patients on cell viability, human foreskin fibroblast (HFF2) cells were treated with CSF samples from individuals with MS and healthy controls. The results inferred that patient-derived CSF significantly declined the survival of HFF2 cells in comparison to the CSF of healthy individuals. This observation implies a cytotoxic environment and characteristic of patients CSF, which could be due to the presence of cellular-damaging factors such as calreticulin (CRT) in the patients CSF. The cytotoxic environment of CSF might reflect ICD occurrence in CNS of the patients and also could explain the progressive essence of the disease.

neuroscience↗

bioRxiv2024

In silico identification of putative causal genetic variants

Understanding the causal genetic architecture of complex phenotypes will fuel future research into disease mechanisms and potential therapies. Here, we illustrate the power of a novel framework: it detects, starting from summary statistics, and across the entire genome, sets of variants that carry non-redundant information on the phenotypes and are therefore more likely to be causal in a biological sense. The approach, implemented in open-source software, is also computationally efficient, requiring less than 15 minutes on a single CPU to perform genome-wide analysis. Through extensive genome-wide simulation studies, we show that the method can substantially outperform existing methods in false discovery rate control, statistical power and various fine-mapping criteria. In applications to a meta-analysis of ten large-scale genetic studies of Alzheimers disease (AD), we identified 82 loci associated with AD, including 37 additional loci missed by conventional GWAS pipeline. Massively parallel reporter assays and CRISPR-Cas9 experiments have confirmed the functionality of the putative causal variants our method points to. Finally, we retrospectively analyzed summary statistics from 67 large-scale GWAS for a variety of phenotypes. Results reveal the methods capacity to robustly discover additional loci for polygenic traits and pinpoint potential causal variants underpinning each locus beyond conventional GWAS pipeline, contributing to a deeper understanding of complex genetic architectures in post-GWAS analyses.

genetics↗